Genetic Studies of Loci Associated with Atrial Fibrillation Atrial fibrillation (AF), which is characterized as the quivering of the atria instead of coordinated contraction, is the most common cardiac arrhythmia, and it is associated with a 2- fold increased risk of mortality and morbidity and a 4- to 5- fold increased risk for stroke. Many risk factors have been identified for AF, however the discovery of heritable components suggests that genetic variation may play a role in AF development. In published genome-wide association studies (GWAS), an AF susceptibility locus has been identified in an intergenic region of chromosome 4q25. We and others have replicated this finding. Additionally, we are part of a consortium that has performed a meta-analysis that has identified five SNPs in this 4q25 region that are independently associated with AF. One of these SNPs is just ~27 Kb downstream from PITX2, the closet gene to this region. PITX2 appears to be an excellent candidate for an AF-causing gene as it is the closest gene to the culprit 4q25 region, and it's known to be important in left/right asymmetry of the heart during development. In addition, Pitx2 +/- mice have been described which are susceptible to arrhythmias when subjected to cardiac electrical pacing. A GWAS identified SNP associated with coronary artery disease on chromosome 9p21 is also located in an intergenic region;and, this region has been shown to have enhancer activity affecting the expression of the nearest genes that are more than 60 Kb away. Thus, we hypothesize that there may be long range enhancers and/or silencers in the 4q25 region and that these may directly affect gene expression of PITX2 or other neighboring genes. To investigate this hypothesis, in vitro and in vivo experiments will be performed to identify and test functional transcriptional regulatory elements in the 4q25 region determine their effects on gene expression of Pitx2 and neighboring genes. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify functional genetic variants associated with atrial fibrillation and thus expand the existing knowledge regarding the genetic changes and their mechanisms that increase ones risk for developing atrial fibrillation. The information gained in these studies may be useful the development of novel and effective treatments, diagnostic tests, and preventative measures for atrial fibrillation.